CN111732087A - Europium-selenium double-doped hydroxyapatite and application thereof in preparing medicine for monitoring and treating osteosarcoma - Google Patents
Europium-selenium double-doped hydroxyapatite and application thereof in preparing medicine for monitoring and treating osteosarcoma Download PDFInfo
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- CN111732087A CN111732087A CN202010587541.4A CN202010587541A CN111732087A CN 111732087 A CN111732087 A CN 111732087A CN 202010587541 A CN202010587541 A CN 202010587541A CN 111732087 A CN111732087 A CN 111732087A
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- 229910052588 hydroxylapatite Inorganic materials 0.000 title claims abstract description 99
- XYJRXVWERLGGKC-UHFFFAOYSA-D pentacalcium;hydroxide;triphosphate Chemical compound [OH-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O XYJRXVWERLGGKC-UHFFFAOYSA-D 0.000 title claims abstract description 99
- GCSIELJPGDPWNK-UHFFFAOYSA-N selanylideneeuropium Chemical compound [Eu]=[Se] GCSIELJPGDPWNK-UHFFFAOYSA-N 0.000 title claims abstract description 61
- 201000008968 osteosarcoma Diseases 0.000 title claims abstract description 31
- 238000012544 monitoring process Methods 0.000 title claims abstract description 8
- 239000003814 drug Substances 0.000 title claims abstract description 4
- 239000011669 selenium Substances 0.000 claims abstract description 31
- 239000013078 crystal Substances 0.000 claims abstract description 18
- 239000010452 phosphate Substances 0.000 claims abstract description 12
- 239000000126 substance Substances 0.000 claims abstract description 9
- 238000010335 hydrothermal treatment Methods 0.000 claims abstract description 7
- BHPQYMZQTOCNFJ-UHFFFAOYSA-N Calcium cation Chemical compound [Ca+2] BHPQYMZQTOCNFJ-UHFFFAOYSA-N 0.000 claims abstract description 3
- 229910001424 calcium ion Inorganic materials 0.000 claims abstract description 3
- 229910000389 calcium phosphate Inorganic materials 0.000 claims abstract description 3
- 238000006243 chemical reaction Methods 0.000 claims description 29
- 239000000047 product Substances 0.000 claims description 28
- 238000002360 preparation method Methods 0.000 claims description 22
- 239000011575 calcium Substances 0.000 claims description 18
- 239000011259 mixed solution Substances 0.000 claims description 13
- 229910052693 Europium Inorganic materials 0.000 claims description 12
- 238000000034 method Methods 0.000 claims description 12
- 229910052711 selenium Inorganic materials 0.000 claims description 12
- 229910019142 PO4 Inorganic materials 0.000 claims description 11
- 239000012266 salt solution Substances 0.000 claims description 11
- 229940091258 selenium supplement Drugs 0.000 claims description 11
- 239000000243 solution Substances 0.000 claims description 11
- 150000000918 Europium Chemical class 0.000 claims description 10
- BVTBRVFYZUCAKH-UHFFFAOYSA-L disodium selenite Chemical group [Na+].[Na+].[O-][Se]([O-])=O BVTBRVFYZUCAKH-UHFFFAOYSA-L 0.000 claims description 10
- 229960001471 sodium selenite Drugs 0.000 claims description 10
- 239000011781 sodium selenite Substances 0.000 claims description 10
- 235000015921 sodium selenite Nutrition 0.000 claims description 10
- OXYOQBAZFDHPBM-UHFFFAOYSA-N [P].[Se] Chemical compound [P].[Se] OXYOQBAZFDHPBM-UHFFFAOYSA-N 0.000 claims description 9
- 159000000007 calcium salts Chemical class 0.000 claims description 9
- AWDWVTKHJOZOBQ-UHFFFAOYSA-K europium(3+);trichloride;hexahydrate Chemical group O.O.O.O.O.O.[Cl-].[Cl-].[Cl-].[Eu+3] AWDWVTKHJOZOBQ-UHFFFAOYSA-K 0.000 claims description 9
- NBIIXXVUZAFLBC-UHFFFAOYSA-K phosphate Chemical compound [O-]P([O-])([O-])=O NBIIXXVUZAFLBC-UHFFFAOYSA-K 0.000 claims description 9
- KPVUHKHVGKSEPB-UHFFFAOYSA-N calcium europium Chemical compound [Ca][Eu] KPVUHKHVGKSEPB-UHFFFAOYSA-N 0.000 claims description 8
- -1 europium ions Chemical group 0.000 claims description 8
- 229940082569 selenite Drugs 0.000 claims description 7
- MCAHWIHFGHIESP-UHFFFAOYSA-L selenite(2-) Chemical compound [O-][Se]([O-])=O MCAHWIHFGHIESP-UHFFFAOYSA-L 0.000 claims description 7
- ZHJGWYRLJUCMRT-UHFFFAOYSA-N 5-[6-[(4-methylpiperazin-1-yl)methyl]benzimidazol-1-yl]-3-[1-[2-(trifluoromethyl)phenyl]ethoxy]thiophene-2-carboxamide Chemical compound C=1C=CC=C(C(F)(F)F)C=1C(C)OC(=C(S1)C(N)=O)C=C1N(C1=C2)C=NC1=CC=C2CN1CCN(C)CC1 ZHJGWYRLJUCMRT-UHFFFAOYSA-N 0.000 claims description 6
- 230000032683 aging Effects 0.000 claims description 6
- 239000007795 chemical reaction product Substances 0.000 claims description 6
- MNNHAPBLZZVQHP-UHFFFAOYSA-N diammonium hydrogen phosphate Chemical compound [NH4+].[NH4+].OP([O-])([O-])=O MNNHAPBLZZVQHP-UHFFFAOYSA-N 0.000 claims description 6
- 229910000388 diammonium phosphate Inorganic materials 0.000 claims description 6
- 235000019838 diammonium phosphate Nutrition 0.000 claims description 6
- 229920001467 poly(styrenesulfonates) Polymers 0.000 claims description 6
- 239000002243 precursor Substances 0.000 claims description 6
- 238000005406 washing Methods 0.000 claims description 6
- VTYYLEPIZMXCLO-UHFFFAOYSA-L Calcium carbonate Chemical compound [Ca+2].[O-]C([O-])=O VTYYLEPIZMXCLO-UHFFFAOYSA-L 0.000 claims description 4
- 239000002270 dispersing agent Substances 0.000 claims description 4
- VSIIXMUUUJUKCM-UHFFFAOYSA-D pentacalcium;fluoride;triphosphate Chemical group [F-].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[Ca+2].[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O.[O-]P([O-])([O-])=O VSIIXMUUUJUKCM-UHFFFAOYSA-D 0.000 claims description 4
- 229940006186 sodium polystyrene sulfonate Drugs 0.000 claims description 4
- 238000001291 vacuum drying Methods 0.000 claims description 4
- LFQSCWFLJHTTHZ-UHFFFAOYSA-N Ethanol Chemical compound CCO LFQSCWFLJHTTHZ-UHFFFAOYSA-N 0.000 claims description 3
- 239000012154 double-distilled water Substances 0.000 claims description 3
- 230000000379 polymerizing effect Effects 0.000 claims description 3
- 238000003828 vacuum filtration Methods 0.000 claims description 3
- PMYDPQQPEAYXKD-UHFFFAOYSA-N 3-hydroxy-n-naphthalen-2-ylnaphthalene-2-carboxamide Chemical compound C1=CC=CC2=CC(NC(=O)C3=CC4=CC=CC=C4C=C3O)=CC=C21 PMYDPQQPEAYXKD-UHFFFAOYSA-N 0.000 claims description 2
- UXVMQQNJUSDDNG-UHFFFAOYSA-L Calcium chloride Chemical compound [Cl-].[Cl-].[Ca+2] UXVMQQNJUSDDNG-UHFFFAOYSA-L 0.000 claims description 2
- 229910000019 calcium carbonate Inorganic materials 0.000 claims description 2
- 239000001110 calcium chloride Substances 0.000 claims description 2
- 229910001628 calcium chloride Inorganic materials 0.000 claims description 2
- BNIILDVGGAEEIG-UHFFFAOYSA-L disodium hydrogen phosphate Chemical compound [Na+].[Na+].OP([O-])([O-])=O BNIILDVGGAEEIG-UHFFFAOYSA-L 0.000 claims description 2
- 238000001035 drying Methods 0.000 claims description 2
- JVYYYCWKSSSCEI-UHFFFAOYSA-N europium(3+);trinitrate;hexahydrate Chemical compound O.O.O.O.O.O.[Eu+3].[O-][N+]([O-])=O.[O-][N+]([O-])=O.[O-][N+]([O-])=O JVYYYCWKSSSCEI-UHFFFAOYSA-N 0.000 claims description 2
- 229910000403 monosodium phosphate Inorganic materials 0.000 claims description 2
- 235000019799 monosodium phosphate Nutrition 0.000 claims description 2
- 239000002245 particle Substances 0.000 claims description 2
- 150000003342 selenium Chemical class 0.000 claims description 2
- AJPJDKMHJJGVTQ-UHFFFAOYSA-M sodium dihydrogen phosphate Chemical compound [Na+].OP(O)([O-])=O AJPJDKMHJJGVTQ-UHFFFAOYSA-M 0.000 claims description 2
- 229960001881 sodium selenate Drugs 0.000 claims description 2
- 239000011655 sodium selenate Substances 0.000 claims description 2
- 235000018716 sodium selenate Nutrition 0.000 claims description 2
- 230000000694 effects Effects 0.000 abstract description 26
- 239000002105 nanoparticle Substances 0.000 abstract description 24
- 150000002500 ions Chemical class 0.000 abstract description 8
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- 230000002980 postoperative effect Effects 0.000 abstract description 2
- 238000000975 co-precipitation Methods 0.000 abstract 1
- 239000000700 radioactive tracer Substances 0.000 abstract 1
- 210000004027 cell Anatomy 0.000 description 39
- OGPBJKLSAFTDLK-UHFFFAOYSA-N europium atom Chemical compound [Eu] OGPBJKLSAFTDLK-UHFFFAOYSA-N 0.000 description 10
- BUGBHKTXTAQXES-UHFFFAOYSA-N Selenium Chemical compound [Se] BUGBHKTXTAQXES-UHFFFAOYSA-N 0.000 description 9
- 238000003917 TEM image Methods 0.000 description 9
- 210000000988 bone and bone Anatomy 0.000 description 8
- 239000000463 material Substances 0.000 description 8
- VHUUQVKOLVNVRT-UHFFFAOYSA-N Ammonium hydroxide Chemical group [NH4+].[OH-] VHUUQVKOLVNVRT-UHFFFAOYSA-N 0.000 description 7
- 235000011114 ammonium hydroxide Nutrition 0.000 description 7
- XLYOFNOQVPJJNP-UHFFFAOYSA-N water Chemical compound O XLYOFNOQVPJJNP-UHFFFAOYSA-N 0.000 description 7
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- VEXZGXHMUGYJMC-UHFFFAOYSA-M Chloride anion Chemical compound [Cl-] VEXZGXHMUGYJMC-UHFFFAOYSA-M 0.000 description 4
- 229910002651 NO3 Inorganic materials 0.000 description 4
- 230000007423 decrease Effects 0.000 description 4
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- 238000001157 Fourier transform infrared spectrum Methods 0.000 description 2
- 229910018143 SeO3 Inorganic materials 0.000 description 2
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- 241001330002 Bambuseae Species 0.000 description 1
- 229910014497 Ca10(PO4)6(OH)2 Inorganic materials 0.000 description 1
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- 208000019926 Keshan disease Diseases 0.000 description 1
- FYYHWMGAXLPEAU-UHFFFAOYSA-N Magnesium Chemical compound [Mg] FYYHWMGAXLPEAU-UHFFFAOYSA-N 0.000 description 1
- 206010028980 Neoplasm Diseases 0.000 description 1
- OAICVXFJPJFONN-UHFFFAOYSA-N Phosphorus Chemical compound [P] OAICVXFJPJFONN-UHFFFAOYSA-N 0.000 description 1
- 235000015334 Phyllostachys viridis Nutrition 0.000 description 1
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- C—CHEMISTRY; METALLURGY
- C01—INORGANIC CHEMISTRY
- C01B—NON-METALLIC ELEMENTS; COMPOUNDS THEREOF; METALLOIDS OR COMPOUNDS THEREOF NOT COVERED BY SUBCLASS C01C
- C01B25/00—Phosphorus; Compounds thereof
- C01B25/16—Oxyacids of phosphorus; Salts thereof
- C01B25/26—Phosphates
- C01B25/32—Phosphates of magnesium, calcium, strontium, or barium
- C01B25/325—Preparation by double decomposition
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K33/00—Medicinal preparations containing inorganic active ingredients
- A61K33/42—Phosphorus; Compounds thereof
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/0019—Fluorescence in vivo characterised by the fluorescent group, e.g. oligomeric, polymeric or dendritic molecules
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- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
- A61K49/00—Preparations for testing in vivo
- A61K49/001—Preparation for luminescence or biological staining
- A61K49/0013—Luminescence
- A61K49/0017—Fluorescence in vivo
- A61K49/005—Fluorescence in vivo characterised by the carrier molecule carrying the fluorescent agent
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- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
- A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
- A61P35/00—Antineoplastic agents
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- B82—NANOTECHNOLOGY
- B82Y—SPECIFIC USES OR APPLICATIONS OF NANOSTRUCTURES; MEASUREMENT OR ANALYSIS OF NANOSTRUCTURES; MANUFACTURE OR TREATMENT OF NANOSTRUCTURES
- B82Y40/00—Manufacture or treatment of nanostructures
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- C01P2002/70—Crystal-structural characteristics defined by measured X-ray, neutron or electron diffraction data
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Abstract
The invention provides europium-selenium double-doped hydroxyapatite and application thereof in preparing a medicament for monitoring and treating osteosarcoma. The nano-grade europium-selenium double-doped hydroxyapatite emitting red fluorescence is prepared by combining wet-chemical coprecipitation and hydrothermal treatment, and has a structure of a beam-shaped needle-shaped polycrystal, wherein Eu/Se ions respectively replace calcium ions and phosphate radicals in a hydroxyapatite crystal lattice. The nanoparticle can be used as a tracer to monitor the growth of osteosarcoma, and has strong anti-osteosarcoma effect. Moreover, the double-element doped hydroxyapatite nanoparticles have high yield and good dispersibility, are suitable for postoperative treatment of osteosarcoma, and have great clinical significance.
Description
Technical Field
The invention belongs to the technical field of biological materials, and particularly relates to europium-selenium double-doped hydroxyapatite for monitoring and treating osteosarcoma and a preparation method thereof.
Background
Hydroxyapatite is the most important inorganic component of human bones and teeth, is often used as a substitute material for repairing bones and teeth, has good histocompatibility, and can induce the regeneration and repair of bones and teeth. At present, the scaffold material prepared by taking the synthetic hydroxyapatite as the base material is widely applied to the repair and replacement of human bones and teeth, such as implant teeth, bone filling materials, artificial bones, artificial joints and the like, and can improve the bone regeneration and repair capability. In addition, the hydroxyapatite has certain anticancer performance and can inhibit the growth of osteosarcoma cells, liver cancer cells, cervical cancer cells and the like.
Europium (Europium, Eu) is a lanthanide rare earth element, has high up-conversion luminous efficiency, and can be excited by infrared light in the range of 800-1000 nm to show red fluorescence. Therefore, europium is commonly used for preparing nano fluorescent probes and is widely applied to the biomedical field. Selenium (Selenium, Se) is one of the essential trace elements for human body, plays an important role in maintaining the normal structure of bone, and is involved in regulating the development and remodeling process of bone tissue. In addition, selenium also has strong effects of resisting oxidation, resisting cancer, enhancing immunity and the like. It can effectively inhibit the growth of osteosarcoma cells and can effectively prevent the progress of Keshan disease, Keshan-beck disease, osteoarthritis and the like.
Currently, new functional materials are being developed in a direction to achieve desired medical applications through structural design and controlled manufacturing, with functional orientation. It is assumed that if the trace elements with anticancer effect and fluorescence effect are added in the host material, the performance of the host material is optimized through host-guest ion exchange, and the host material is endowed with new connotation, which adds new connotation for development of new functions and materials and exploration of scientific rules and provides a good direction. At present, the research on the hydroxyapatite modified by element doping is mature, for example, selenium element is doped into the hydroxyapatite crystal lattice to prepare the selenium-doped hydroxyapatite (a hydroxyapatite doped with selenium and a preparation method thereof, patent number: 201110127119.1); europium is doped into hydroxyapatite (a preparation method of europium-doped hydroxyapatite fluorescent nanoparticles, patent number: 201310435997.9); strontium is doped into hydroxyapatite (a preparation method of a strontium-doped hydroxyapatite composite film, the patent number is 201810637389.9); doping magnesium into hydroxyapatite (magnesium-doped hydroxyapatite and its preparation method, patent No. 201810321533.8), etc. However, no research report on the hydroxyapatite nano material doped with selenium and europium is found at present, and how to dope selenium with an anti-osteosarcoma effect and europium with an up-conversion red fluorescence effect into a hydroxyapatite lattice structure is still a technical problem.
Disclosure of Invention
The invention aims to solve the problems and provides europium-selenium double-doped hydroxyapatite nanoparticles for monitoring and treating osteosarcoma and a preparation method thereof.
In order to solve the technical problems, the technical scheme adopted by the invention is as follows:
a molecular structure of europium-selenium double-doped hydroxyapatite is an apatite structure, wherein calcium ions and phosphate radicals in hydroxyapatite crystal lattices are respectively substituted by europium and selenium ions. The molar ratio of calcium-europium bimetallic atoms to phosphorus-selenium nonmetallic atoms in the chemical structure is 1-3, meanwhile, the atomic ratio of Se to P is less than or equal to 10%, and the atomic ratio of Ca to Eu is 58-70%.
Preferably, the molar ratio of calcium europium to phosphorus selenium in the chemical structure is 1.667, and the atomic ratio of Se to P is 10% and the atomic ratio of Ca to Eu is 64.28%.
Hydroxyapatite (HA) chemical structural formula: ca10(PO4)6(OH)2；
The chemical structural formula of the selenium-doped hydroxyapatite (SeHA) is as follows: ca10(PO4)x(SeO3)(18-3x)÷2(OH)2(wherein 0)<x<6) When x =5.625, the Se/P atomic ratio is 10%, i.e., the degree of substitution. (because of the Se/P atomic ratio>Product phase is impure at 10%, so the fixed Se/P substitution degree is 10% when preparing the product);
the chemical structural formula of the europium selenium double-doped hydroxyapatite (EuSeHA) is as follows: caxEu(20-2x)÷3(PO4)y(SeO3)(18-3y)÷2(OH)2(wherein 0)<x<10，0<y<6) The above products were synthesized under conditions of (Ca + Eu)/(Se + P) =10/6=1.667, and when y =5.625, the Se/P atomic ratio was 10%, i.e., different Eu-doped SeHA products were synthesized with a fixed Se/P substitution degree of 10% (EuSeHA crystals, Ca/Eu ratio as a variable).
Furthermore, the particle size of the europium-selenium double-doped hydroxyapatite is in a nanometer level, and the europium-selenium double-doped hydroxyapatite is a fusiform polycrystal formed by polymerizing multi-needle-shaped crystals, wherein the length of the fusiform crystal is 100-200nm, and the width of the fusiform crystal is 20-30 nm.
A preparation method of europium selenium double-doped hydroxyapatite comprises the following specific steps:
(1) controlling the pH value of the solution to be 9-11 and the reaction temperature to be 50-70 ℃ and keeping the pH value and the reaction temperature all the time, and slowly dripping the mixed solution of phosphate and selenite into the mixed solution of calcium salt and europium salt to ensure that the mixed solution reacts completely;
(2) after the first step of reaction is finished for 60-120 minutes, transferring the product precursor into a reaction kettle, and carrying out hydrothermal treatment at 100-140 ℃ for 30-45 minutes under 1 atmospheric pressure;
(3) after the reaction is finished, taking out a reaction product, and aging at room temperature for 20-24 hours;
(4) and dialyzing and washing the product for several times by using sterilized double distilled water to remove impurity ions such as free sodium ions, chloride ions, nitrate radicals and the like, and drying in vacuum to obtain the europium-selenium double-doped hydroxyapatite.
A preparation method of nano-grade europium selenium double-doped hydroxyapatite can also comprise the following steps:
(1) controlling the pH value of the solution at 9-11 and the reaction temperature at 50-70 deg.C, and slowly dripping the mixed solution of phosphate and selenite into the calcium salt solution to make them react completelyThen adding proper amount of dispersing agent PSS sodium polystyrene sulfonate (5% -10%)w/v）；
(2) Dropwise adding a europium salt solution into the reaction solution obtained in the step (1), and controlling the pH value of the reaction solution to be 9-11;
(3) after the europium salt solution is dripped, transferring all the product precursors into a reaction kettle, and carrying out hydrothermal treatment at 100-140 ℃ for 30-45 minutes under 1 atmospheric pressure;
(4) after the reaction is finished, taking out a reaction product, and aging at room temperature for 20-24 hours;
(5) and (4) centrifugally washing the reaction product in the step (4) for several times by using absolute ethyl alcohol to remove impurity ions such as free sodium ions, chloride ions, nitrate radicals and the like, and performing vacuum filtration and drying to finally obtain the nano-grade europium-selenium double-doped hydroxyapatite.
Preferably, the calcium salt comprises any one of calcium nitrate tetrahydrate, calcium chloride, or calcium carbonate;
preferably, the phosphate is any one of diammonium hydrogen phosphate, disodium hydrogen phosphate, or sodium dihydrogen phosphate.
Preferably, the selenium salt comprises sodium selenite or sodium selenate.
Preferably, the europium salt is europium chloride hexahydrate or europium nitrate hexahydrate.
Preferably, the reagent for adjusting the pH value is ammonia water (NH)3•H2O）。
The invention has the following advantages:
the product prepared by the invention is a novel europium-selenium double-doped hydroxyapatite nano material, and as a preferred scheme, the optimal fixed value of the molar ratio of calcium europium to phosphorus selenium is 1.667, the atomic ratio of selenium to phosphorus is 10%, and the atomic ratio of Ca to Eu is 64.28%. The europium-selenium double-doped hydroxyapatite is a fusiform polycrystal polymerized by multi-needle crystals. The spindle crystal has nanometer size of 100-200nm and 20-30nm width, and has excellent up-converting red fluorescence effect, and can be taken by osteosarcoma cell to inhibit its growth and proliferation. The preparation method of the nanoparticle has the characteristics of environmental protection, energy conservation, simple and convenient operation and low cost, has better monitoring of osteosarcoma growth and certain osteosarcoma resistance effect, can be industrially produced, and has wide application prospect in osteosarcoma postoperative treatment and early monitoring of recurrence.
Drawings
The present invention will be described in further detail with reference to the accompanying drawings and embodiments.
Fig. 1 is XRD diffractograms of hydroxyapatite, europium-doped hydroxyapatite prepared in example 1, and europium selenium-double-doped hydroxyapatite obtained in example 1.
Fig. 2 shows FTIR spectra of the europium-doped hydroxyapatite prepared in example 1 and the europium-selenium double-doped hydroxyapatite prepared in example 1.
Fig. 3 is a TEM image of the modified hydroxyapatite nanomaterial, wherein (1) is a TEM image of the hydroxyapatite nanomaterial, (2) is a TEM image of the selenium-doped hydroxyapatite nanomaterial, (3) is a TEM image of the europium-doped hydroxyapatite nanomaterial, (4) is the europium-selenium double-doped hydroxyapatite product obtained in example 1, and (5) is the europium-selenium double-doped hydroxyapatite product obtained in example 2.
Fig. 4 is a graph of the upconversion luminescence effect of the europium selenium double-doped hydroxyapatite obtained in example 2 when Se/P =10% and Ca/Eu = 64.28%.
FIG. 5 shows the uptake and intracytoplasmic localization of europium selenium double-doped hydroxyapatite obtained in example 2 by osteosarcoma cells, wherein (1) the nanoparticles aggregate at the cell membrane edge at 30 min; (2) the nuclear periphery aggregation map of the nanoparticle at 1 hour; (3) is (2) the intracytoplasmic map of the single cell when it reacts with the nanoparticle for 1 hour.
Fig. 6 is a graph showing the effect of europium selenium double-doped hydroxyapatite obtained in example 2 in osteosarcoma treatment, wherein the graph shows the distribution density change of different nanoparticles co-cultured with osteosarcoma cells for 48 hours, wherein (a) is a blank control group, (B) is a pure hydroxyapatite control group, (C) is a europium-doped hydroxyapatite control group, and (D) is a europium selenium double-doped hydroxyapatite experimental group.
FIG. 7 is a graph showing the change in the proliferation activity of osteosarcoma cells, wherein A is the change in the proliferation activity of osteosarcoma cells after 48 hours of the action of different nanoparticles; and B is the change of the osteosarcoma cell proliferation activity after the europium-selenium double-doped hydroxyapatite nanoparticles with different doping amounts act for 48 hours.
Detailed Description
Example 1
The preparation method comprises the steps of selecting analytically pure calcium nitrate tetrahydrate, analytically pure diammonium phosphate, analytically pure sodium selenite, analytically pure europium chloride hexahydrate and analytically pure ammonia water, and synthesizing the europium-doped selenium-doped nano-hydroxyapatite with the Se/P atomic ratio of 10% and the Ca/Eu atomic ratio of 64.28%. The method comprises the following specific steps:
(1) 12.398g of analytically pure calcium nitrate tetrahydrate and 4.156g of analytically pure europium chloride hexahydrate are jointly dissolved in 320ml of distilled water (calcium-europium mixture); dissolving 0.0083g of analytically pure diammonium phosphate and 0.0083g of analytically pure sodium selenite in 320ml of distilled water (phosphorus-selenium mixed solution), and stirring at room temperature until the solutions are completely dissolved;
(2) adjusting the pH value of the calcium-europium mixed solution to 11 by using ammonia water, and increasing the temperature to 65 ℃ by using a constant-temperature magnetic stirrer;
(3) slowly dripping the phosphorus-selenium mixed solution obtained in the step (1) into the calcium-europium mixed solution under the condition of keeping the step (2), and controlling the dripping speed to keep the dripping process for 100 minutes;
(4) in the step (3), when the reaction lasts for 120 minutes, transferring the product precursor into a reaction kettle, and carrying out hydrothermal treatment at 120 ℃ for 45 minutes under 1 atmospheric pressure;
(5) after the step (4) is finished for 30 minutes, taking out the reaction kettle, cooling the reaction kettle at room temperature, properly dropwise adding ammonia water to maintain the pH value of the product solution to be 11, and aging the product for 24 hours;
(6) and (5) after the reaction in the step (5) is finished, dialyzing and washing the obtained europium-selenium double-doped hydroxyapatite product by using sterilized double-distilled water, changing water for 1 time every 2 hours, repeatedly maintaining for 3 days to remove impurity ions such as free sodium ions, chloride ions, nitrate radicals and the like, and finally performing vacuum drying to obtain the europium-selenium double-doped hydroxyapatite nano powder.
Referring to fig. 1, fig. 1 is an XRD diffractogram of the europium selenium double-doped hydroxyapatite, and it can be seen that the obtained product is an apatite phase under the condition of the doping ratio. In the figure, the preparation method of only europium-doped hydroxyapatite is the XRD diffraction pattern of the product obtained by the preparation method without adding sodium selenite raw material. The preparation method of the hydroxyapatite in the figure is an XRD diffraction pattern of a product obtained by a preparation method without adding europium chloride hexahydrate and sodium selenite raw materials.
Referring to fig. 2, fig. 2 is an XRD diffractogram of europium selenium double-doped hydroxyapatite and an XRD diffractogram of europium doped hydroxyapatite, from which it can be seen that the reaction product has distinct phosphate, selenite and hydroxyl peaks; thus, the product powder was found to contain phosphate, selenite and hydroxyl groups.
Referring to fig. 3, (1) in fig. 3 is a TEM image of the hydroxyapatite prepared without adding raw materials of europium chloride hexahydrate and sodium selenite in the above preparation method, wherein the morphology is in a chain sphere shape. Fig. 2 is a TEM image of hydroxyapatite prepared by adding sodium selenite raw material in the above preparation method, wherein the product with a Se/P ratio of 10% is in a bamboo leaf shape. FIG. 3 is a TEM image of the hydroxyapatite prepared by adding the raw material europium chloride hexahydrate in the above preparation method, wherein the product with Ca/Eu ratio of 64.28% is in a filament shape. FIG. 4 is a TEM image of europium selenium double-doped hydroxyapatite prepared in example 1, designated as HA Eu/Se-1, which is seen to be shaped as a nanorod-like polycrystal having a length of about 50nm and a width of about 10 to 15 nm.
Example 2
The preparation method comprises the steps of selecting analytically pure calcium nitrate tetrahydrate, analytically pure diammonium phosphate, analytically pure sodium selenite, analytically pure europium chloride hexahydrate and analytically pure ammonia water, and synthesizing the europium-doped selenium-doped nano-hydroxyapatite with the Se/P atomic ratio of 10% and the Ca/Eu atomic ratio of 64.28%. The method comprises the following specific steps:
(1) 12.398g of analytically pure calcium nitrate tetrahydrate is dissolved in 320ml of distilled water (calcium salt solution), 4.156g of analytically pure europium chloride hexahydrate is dissolved in 320ml of distilled water (europium salt solution), 0.0083g of analytically pure diammonium hydrogen phosphate and 0.0083g of analytically pure sodium selenite are dissolved in 320ml of distilled water together (phosphorus-selenium mixed solution), and stirring is carried out at room temperature until complete dissolution is achieved;
(2) adjusting the pH value of the calcium salt solution to 11 by using ammonia water, and increasing the temperature to 65 ℃ by using a constant-temperature magnetic stirrer;
(3) slowly dripping the phosphorus-selenium mixed solution obtained in the step (1) into the calcium salt solution under the condition of keeping the condition of the step (2), and controlling the dripping speed to ensure that the dripping process lasts for 60 minutes;
(4) in the step (3), after the reaction was continued for 10 minutes, 3ml of 10%, (3 ml)w/v) PSS sodium polystyrene sulfonate as dispersant;
(5) after the step (4) is finished for 20 minutes, slowly dropwise adding the europium salt solution prepared in the step (1) into a reaction container, keeping the dropwise adding process for 30 minutes, and adding ammonia water to adjust the pH value of the reaction solution to 11;
(6) after the reaction in the step (5) is finished, transferring all the product precursors into a reaction kettle, and carrying out hydrothermal treatment at 120 ℃ for 45 minutes under 1 atmosphere;
(7) taking out the europium selenium double-doped hydroxyapatite product obtained in the step (6), and aging at room temperature for 24 hours;
(8) and (3) washing the product obtained in the step (7) with absolute ethyl alcohol for 3-5 times, centrifuging at 5000rpm for 15min, discarding the supernatant to remove impurity ions such as free sodium ions, chloride ions, nitrate ions and the like, and performing vacuum filtration and drying to finally obtain the nano-grade europium-selenium double-doped hydroxyapatite.
Referring to fig. 1 and 2, the XRD and FTIR spectra of the europium selenium double doped hydroxyapatite obtained in example 2 are the same as those of example 1, and it is demonstrated that the same products obtained by the above 2 different preparation methods are all apatite substances, and the powder of the product contains phosphate, selenite and hydroxyl groups. Referring to (5) in FIG. 3, which is a TEM image of the europium selenium double-doped hydroxyapatite prepared in example 2 and designated as HA: Eu/Se-2, it can be seen that it is shaped as a fusiform polycrystal formed by polymerizing a plurality of needle-shaped crystals, the fusiform crystal having a length of about 200nm and a width of about 20 nm. Referring to fig. 4, fig. 4 is a graph of the upconversion luminescence effect of the europium selenium double-doped hydroxyapatite, and it can be seen from the graph that the double-doped nanoparticles exhibit bright red fluorescence under 998nm infrared excitation light. Referring to fig. 5, fig. 5 shows the intracytoplasmic localization and luminescence effect of the europium selenium double-doped hydroxyapatite nanoparticles after being taken up by osteosarcoma cells, and it can be seen from the figure that: the europium-selenium double-doped hydroxyapatite nanoparticles are easy to be absorbed by osteosarcoma cells, can be positioned at the outer edge of a cell membrane within 30min of contact with the cells, can be positioned at the edge of a cell nucleus or even in the cell nucleus along with the prolonging of time, and can inhibit the proliferation activity of the osteosarcoma cells when being positioned for 1h after contact. Referring to fig. 6, fig. 6 shows the cell distribution density change of europium selenium double-doped hydroxyapatite nanoparticles and osteosarcoma cells in 48 hours of co-culture, wherein cells of a normal control group without the nanoparticle effect are densely distributed, and gaps between the cells are narrowed; after the pure hydroxyapatite not doped with elements acts, partial cells become round, gaps between the cells become wider, and even a small amount of cells die and are suspended in the culture solution; the cells which are subjected to the action of the pure europium-doped hydroxyapatite also have the morphological change, the cell gaps are widened, and the cell density is reduced; more obviously, most of the cells after the europium-selenium double-doped hydroxyapatite acts are detached from the wall and suspended in the culture solution, the intercellular space is increased, and gaps formed by fusion of the detached wall regions are easily seen at the bottom of the culture plate, so that the autocrine and paracrine actions of the cells are inhibited, the survival microenvironment of the cells is changed, and the growth of the cells is seriously influenced. Referring to fig. 7, fig. 7 shows the change of cell proliferation activity after the europium-selenium double-doped hydroxyapatite nanoparticles are co-cultured with osteosarcoma cells for 48 hours, as can be seen from fig. 7A: compared with the hydroxyapatite which is not doped with elements, is doped with pure europium or is doped with pure selenium, the europium-selenium double-doped hydroxyapatite has better effect of inhibiting the proliferation activity of osteosarcoma, and compared with the normal control group cells without the nanoparticle effect, the cell activity of the europium-selenium double-doped nanoparticles is reduced by about 60 percent, so that the cell distribution density is correspondingly reduced, and the result is consistent with the result shown in the figure 6D. More interestingly, europium selenium double-doped nanoparticles with different doping amounts, which are synthesized under the condition that the atomic ratio of Se to P is 10%, have a certain dosage relationship on the proliferation activity of osteosarcoma cells: as shown in fig. 7B, compared to a normal control cell without nanoparticle effect, the cell proliferation activity of osteosarcoma cell decreases with the increase of Ca/Eu atomic ratio in the europium-selenium double-doped nanoparticle, wherein the cell activity decreases by approximately 60% after the nanoparticle with Ca/Eu ratio of 0.6428 is acted, and further increases with the Ca/Eu ratio until Ca/Eu =1.0 or even Ca/Eu =1.5, the cell activity decreases by approximately 90%, although the europium-selenium double-doped nanoparticle with the doping dose has the strongest killing power on tumor cells at this time, under the condition of the high doping dose (Ca/Eu ≥ 1.0), the stability of the europium-selenium double-doped hydroxyapatite crystal gradually decreases, the crystal cracks and even disintegrates, the released Se and Eu ion doses are too high, and it is easy to generate a large toxic effect on normal tissue cells: for example, Se ions are easy to cause acute poisoning of the body, myocardial inhibition, blood pressure reduction, respiratory depression, growth and development retardation of children and the like; eu ions are complexed with chromatin DNA in normal cell nuclei, so that the normal structure of the DNA is changed, and cell mutation is promoted.
Therefore, in order to obtain the europium selenium double-doped hydroxyapatite crystal with high efficiency, low toxicity and good stability by combining the results, the Ca/Eu atomic ratio is preferably 64.28 under the condition that the fixed Se/P atomic ratio is 10% in the preparation process of the europium selenium double-doped hydroxyapatite crystal for treating osteosarcoma in the future.
Although the present invention has been described in detail with reference to the preferred embodiments, it will be understood by those skilled in the art that various changes may be made and equivalents may be substituted without departing from the spirit and scope of the invention as defined in the appended claims.
Claims (10)
1. The europium-selenium double-doped hydroxyapatite is characterized in that the molecular structure is an apatite structure, and calcium ions and phosphate radicals in hydroxyapatite crystal lattices are respectively substituted by europium ions and selenium ions.
2. The europium selenium double-doped hydroxyapatite according to claim 1, wherein the molar ratio of calcium europium bimetallic atoms to phosphorus selenium non-metallic atoms in the chemical structure is 1-3, the atomic ratio of Se to P is less than or equal to 10%, and the atomic ratio of Ca to Eu is 58-70%.
3. The europium selenium double-doped hydroxyapatite according to claim 2, wherein the chemical structure thereof has a molar ratio of calcium europium to phosphorus selenium of 1.667, and an atomic ratio of Se to P of 10% and an atomic ratio of Ca to Eu of 64.28%.
4. The europium selenium double-doped hydroxyapatite of claim 3, wherein the particle size of the europium selenium double-doped hydroxyapatite is in the nanometer level, and the europium selenium double-doped hydroxyapatite is a fusiform polycrystal formed by polymerizing multi-needle crystals, wherein the fusiform crystal has a length of 100-200nm and a width of 20-30 nm.
5. The method for preparing europium selenium double-doped hydroxyapatite according to any one of claims 1 to 4, wherein the method comprises the following steps:
(1) slowly dripping the mixed solution of phosphate and selenite into the mixed solution of calcium salt and europium salt under the conditions of pH of 9-11 and temperature control of 50-70 ℃, and reacting for 60-120 minutes;
(2) after the reaction in the step (1) is finished, transferring the product precursor into a reaction kettle, and carrying out hydrothermal treatment at 100-140 ℃ for 30-50 minutes;
(3) after the reaction is finished, taking out the reaction product, and aging for 20-24 hours at room temperature;
(4) and dialyzing and washing the product for multiple times by using sterilized double distilled water, and drying in vacuum to obtain the europium-selenium double-doped hydroxyapatite.
6. The method for preparing nano-grade europium selenium double-doped hydroxyapatite according to claim 5, wherein the preparation method further comprises the following steps:
(1) slowly dripping the mixed solution of phosphate and selenite into the calcium salt solution under the conditions that the pH value is 9-11 and the temperature is controlled to be 50-70 ℃, and then adding the dispersant sodium polystyrene sulfonate to completely react;
(2) dropwise adding a europium salt solution into the reaction solution obtained in the step (1), and controlling the pH value of the reaction solution to be 9-11;
(3) after the europium salt solution is dripped, transferring all the product precursors into a reaction kettle, and carrying out hydrothermal treatment at 100-140 ℃ for 30-50 minutes;
(4) after the reaction is finished, taking out a reaction product, and aging for 20-24 hours at room temperature;
(5) and (3) centrifugally washing with absolute ethyl alcohol for a plurality of times, and then carrying out vacuum filtration and drying to finally obtain the nano-grade europium-selenium double-doped hydroxyapatite.
7. The method for preparing europium selenium double-doped hydroxyapatite according to claim 5 or 6, wherein the calcium salt comprises any one of calcium nitrate tetrahydrate, calcium chloride, or calcium carbonate; the phosphate is any one of diammonium hydrogen phosphate, disodium hydrogen phosphate or sodium dihydrogen phosphate.
8. The method for preparing europium selenium double-doped hydroxyapatite according to claim 5 or 6, wherein the selenium salt is sodium selenite or sodium selenate; the europium salt is europium chloride hexahydrate or europium nitrate hexahydrate.
9. The method for preparing europium selenium double-doped hydroxyapatite according to claim 5 or 6, wherein the dispersant sodium polystyrene sulfonate is 5% -10% (by mass)w/v）。
10. Use of europium selenium double doped hydroxyapatite according to any one of claims 1 to 4 or prepared according to any one of claims 5 to 8 for the preparation of a medicament for monitoring and treating osteosarcoma.
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